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85 Cards in this Set

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Wolf-
Hirschhorn syndrome
the deletion of material from
the short arm of chromosome 4,
Wolf-Hirschhorn syndrome facial appearance
The eyes are set widely apart and
the nose is prominent
Chromosomes condense into more compact structures during
cell division. Condensation begins in
prophase when the nuclear
membrane disperses
Chromosomes are most easily visualized at
metaphase, when they are lined at the center of the cell.
Down syndrome, a relatively common disorder characterized by
facial appearance, decreased muscle tone, developmental
impairment and, sometimes, congenital malformation of the heart or
other organs
individuals
with Down syndrome have 47 chromosomes, including
an extra copy of
what appeared to be the smallest chromosome, designated 21.
Turner syndrome
Females
with short stature, lack of secondary sexual development, and infertility. have 45 chromosomes, including
only a single sex chromosome, an X
Males with Klinefelter syndrome
(male external genitals but slight breast development, tall stature, and
infertility) were found to have 47 chromosomes with an XXY karyotype.
aneuploidy
aneuploidy (a complete diploid set
of chromosomes with one or more extra or missing chromosomes
Most common trisonomies
Patau Syndrome Trysonomy 13
Edwards Syndrome Trysonomy 18
Down Syndrome Trisonomy 21
Monosomy X is
turner syndrome
phytohemagglutinin,
stimulate
the division of peripheral blood T lymphocytes
colchicine
inhibits the mitotic spindle accumulating cells at metaphase
Metaphase chromosomes contain two strands
chromatids, having replicated their genetic material at
interphase. The chromatids remain attached at the centromere, which
divides the most chromosomes into a short arm and a long arm.
The
short arm is abbreviated
for petit,
long arm is abbreviated
q (because it follows p.)
The three largest were designated
group A. The first and third have their centromeres near the center and
are referred to as
The second has a centromere slightly
displaced from center and is called
metacentric
submetacentric
Group B consists
of two large chromosomes each with its centromere located
toward the
end of the chromosome, also designated as submetacentric.
Group C
includes seven pairs plus the X chromosome.Most members of this
group are
submetacentric
The three pairs of group D chromosomes
have centromere is near the end of the chromosome and are called
acrocentric
Group G contains two very small
acrocentrics, also with ribosomal DNA comprising substantial portions
of the short arms, and one of these is the
extra chromosome of Down
syndrome. .
The Y chromosome is a
small submetacentric
Q banded karyotype
staining
with fluorescent dye quinacrine, was introduced because it was
hypothesized that variations of base sequence would exist along the
lengths of chromosomes and could be revealed by differential binding
of the alkylating agent quinacrine mustard, which reacts with G-C base
pairs.
non-alkylating analog quinacrine dihydrochloride elicits
bands of bright and dull fluorescence due to fluorescence enhancement
in AT-rich DNA and quenching in GC-rich regions.
G banded karyotype
pretreatment of chromosomes with a variety of agents (e.g., the
protease trypsin) followed by staining with Giemsa. The same bands
were seen as were elicited by quinacrine,
most bright fluorescent bands
seen with
quinacrine or darkly stained with Giemsa
R banded karyotype
Useful for defining chrosomes ends
A pattern that is the reverse of
Q- or G-banding was produced with another staining technique
designated
R-banding
An approach to staining condensed
chromosome material near the centromeric regions was called
Cbanding
T-bands,
which stained
the ends of chromosomes
NOR staining, which
highlights
the nucleolus organizer regions of the acrocentric
chromosomes.
Histone octomer subunits
H2A-H2B-H3-H4
Giemsa light bands are rich in expressed sequences and high in GC content. Alu repeated sequences are
GC rich and are found in or near expressed genes
Giemsa dark band, have less expressed genes a high
AT content
what regions predominate in the Giemsa dark bands
L1 repeated sequences which are rich in AT
If chromosomes are studied early in mitosis before they are highly
compacted or if compaction is inhibited by treatment with a DNA
intercolating agents such as ethidium bromide..what can we see?
very fine detail can be
discerned.
The gain of an entire chromosome, such as occurs in Down syndrome,
is the result of
nondisjunction. This involves missegregation of
chromosomes at meiosis or mitosis with two copies of a particular
chromosome going to one cell and no copy to the other cell.
Embryos monosomic for an autosome usually do not survive. Most
autosomal trisomies are also nonviable, except for
trisomies 13, 18, and
21.
If non-disjunction occurs during mitosis in the developing embryo
mosaicism results, wherein the embryo consists of a mixture of
trisomic and normal cells (again the monosomic cells usually die except
for monosomy X.)
see
pg 25 types of chromosomal anomalies
A piece of a
chromosome may be lost
results in monosomy
lost by deletion or may be duplicated
trisomy for
the genes
Another intra-chromosomal rearrangement is formation of a
ring. This usually arises from breakage
of the two ends and their
subsequent fusion into a ring structure.
Translocations usually arise as reciprocal exchanges. If
no material is lost or gained the translocation is said to be
balanced
It is estimated that approximately 0.2% of
individuals carry and asymptomatic chromosomal rearrangement. If one
comes to medical attention, it is usually as a consequence of
the
generation of unbalanced gametes during meiosis, leading to
spontaneous abortion or the birth of a child with congenital anomalies
In the early days of
cytogenetics it was found that at the two ends of a chromosome there is
a sort of cap referred to as
the telomere
Breakage of the chromosome
leads to formation of a “sticky end,”which tends to be unstable. This is
avoided if
the rearrangement involves exchange of material between
two chromosomes
Reduction in telomerase activity has been hypothesized to be
responsible for
the accumulation of chromosomal aberrations that
accompany cell senescence or malignancy.
Balanced chromosomal rearrangements can spawn gametes with
genetic imbalance due to
aberrant segregation during meiosis
Meiosis
consists of two rounds of cell division and effects a reduction from
the
diploid to haploid state in germ cells.
Meiotic pairing between chromosomes involved in a balanced
translocation requires
a complex association of four chromosomes: the
two involved in the exchange and the two homologs
When the first
anaphase occurs these chromosomes can separate in several ways. If
the two normal homologs go to one cell and the two involved in the
exchange go to another, the resulting gametes will be genetically
balanced: either normal or both having rearranged chromosomes
Genetic imbalance will result if
germ cells get one normal
chromosome and one rearranged chromosome
The translocation
complex can also segregate so that three chromosomes go to one cell
and only one to the other. Rarely, all four chromosomes can go to the
same cell. Obviously
major genetic imbalance results in these
instances.
Translocations account for a minority of cases of
Down syndrome
Translocations between acrocentric chromosomes in which the long
arms fuse at the centromeres are referred to as
Robertsonian
translocations.
A Robertsonian translocation carrier has 45
chromosomes but is phenotypically normal. If, however, both the
translocated chromosome and a normal 21 go to the same germ cell at
meiosis, fertilization will result in
trisomy 21.
It is important to identify translocation cases because
the
carrier is at risk of having additional offspring with trisomy
Robertsonian
translocations Can be present in many members of a family, all of
whom are at risk of
having children with Down syndrome
Pairing between homologs where one chromosome is
inverted requires formation of a loop. Crossing over with in the loop
leads to duplication and efficiency of genetic material. If the inversion
does not include the centromere, called a
paracentric inversion
paracentric inversion lead to
dicentric and acentric chromosomes result. These are usually unstable
at mitosis and lead to non-viable phenotypes
Inversions that involve
the centromere, called pericentric inversions, lead to
lead to partial trisomies
and monosomies, some of which may be viable.
Visualization of chromosome structure requires access to dividing cells.
These can be obtained from the fetus by
chorionic villus biopsy or
amniocentesis
why is only the mother's age a factor in having a child with down syndrome
in the male, meiosis begins after puberty and lasts only a few weeks. Continued mitotic division of spermatogonia may increase the rate of
gene mutation, but the rate of nondisjunction is lower than in oogenesis.
When nondisjunction occurs during mitosis rather then meiosis the
result is
chromosomal mosaicism
Generally, Down syndrome due
to trisomy 21 mosaicism is indistinguishable from
Downs syndrome in
general
If trisomy 21 mosaicism is detected
prenatally or at birth, it is difficult to predict whether a full Down
syndrome phenotype will occur. The exact proportion of trisomy 21 cells
may differ from tissue to tissue. A low percentage of abnormal cells in
peripheral blood does not necessarily predict
a low proportion in heart
or brain.
Nonmosaic
trisomy, for most chromosomes, results in
miscarriage during the first
trimester
Trisomy 8 has been seen clinically only when
it
is mosaic and as such produces a characteristic syndrome. In contrast,
complete trisomy 8 results in miscarriage.
There is evidence that only a subset of genes on chromosome 21 is
responsible for the Down syndrome phenotype. Some individuals have
been found to have trisomy for only a small region of chromosome 21
due to
segregation of an unbalanced translocation
cytogenetic analysis under light microscope can only be done for
sequences of more than a million bp
DiGeorge Syndrome
lack of para and thyroid glands has submicroscopic mutations. It shows no visual deletions under light microscopy
Genomic Imprinting
Some genes are not equally expressed from the maternal and paternal alleles. Rather either one of them is preferentially expressed at least during early development. . If the deleted allele is the one that it is mostly normally active, the gene will be absent even though one copy is retained
The effects of imprinting first came to light in humans through studies of
rare individuals affected with cystic fibrosis who also had severe growth
and developmental delay. They were found to have inherited the cystic
fibrosis gene mutation, along with other genes on chromosome 7, from
just one parent. This is called
uniparental disomy
Uniparental disomy
is believed to be due to
loss of one chromosome in a trisomic
conceptus
Trisomy 7 would be nonviable, but if in early development one of the
three copies of chromosome 7 in a trisomic embryo is lost by
disjunction,
the normal number of chromosomes would be restored. If
the remaining copies of chromosome 7 are derived from the same
parent, however, uniparental disomy results, which will have phenotypic
consequences if the chromosome includes imprinted genes.
Prader Willi and Angelmann syndromes are associated with
deletions of same region of chromosome 15
Phenotype of chromosome 15 region is
If maternal sequences are deleted
Prader Willi
Angelmann
In some cases of Prader willi-Angelmann syndrome, no deletions occur but instead there is
uniparental disomy for the paternal (giving Angelmann) or for the maternal (giving prader)
fragile X syndrome
The fragile
X site is seen only if the cells are grown in culture medium that is
deficient in thymidine and folic acid, or in medium supplemented with
fluorodeoxyuridine, an inhibitor of thymidylate synthetase.
Depletion of
nucleotide pools stimulates the expression of
fragile sites such as
fragile X. There are other folate-sensitive fragile sites in the human
genome, but fragile X is the only one associated with a phenotype.
Not all cells of a male with fragile X syndrome display
the fragile X
chromosome (5-50%)
Fragile X syndrome offspring carrier percentage
50% of the male offspring and 30% of the female offspring of a carrier
mother will develop fragile X syndrome
The
cytogenetic test for fragile X is not as reliable for
females as for males,
however. A positive test in a female is significant, but many female
carriers for fragile X have normal cytogenetic studies.
males appear to be obligate carriers but do not themselves
manifest signs of the condition The phenomenon of nonmanifesting
males is called the
Sherman paradox.